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MYELODYSPLASTIC SYNDROMES 2009

MYELODYSPLASTIC SYNDROMES 2009. Marion Sternbach, MD, FRCP(C) FACP. Myelodysplastic Syndromes ( MDS ). Definition: Myelo = marrow in Greek Dys = irregular in Greek Plasia = proliferation in Greek

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MYELODYSPLASTIC SYNDROMES 2009

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  1. MYELODYSPLASTIC SYNDROMES2009 Marion Sternbach, MD, FRCP(C)FACP

  2. Myelodysplastic Syndromes ( MDS ) • Definition: Myelo = marrow in Greek Dys = irregular in Greek Plasia = proliferation in Greek MDS is a heterogenous stem cell disease with a very active and abnormal proliferation of hematopoiesis in the bone marrow with asynchronous and delayed maturation of the different cell lines and early apoptosis ( cell death ) leading to ineffective hematopoiesis and peripheral blood (PB) cytopenia.

  3. Myelodysplasia (MDS)Patho-physiology • 1. Since the stem cell is diseased any or all of the erythroid, myeloid or megakaryocytic cell lines may be affected. • 2. An acquired somatic mutation of the stem cell CD 34 may cause one or several cytogenetic anomalies, influencing to a great extent the clinical evolution of the disease. • 3. In addition to peripheral cytopenia, there is also shortened survival of the affected cells as well as qualitative deficiencies of these cells: e.g. defic. Chemotaxis of granuloc., bleeding, etc.

  4. Myelodysplasia (MDS)Nucleo – Cytoplasmic asynchrony Giant metamyelocyte Immature nucleus,loose Chromatin. Hemoglobinized orthochromic erythroblast with still immature Alk. PO4-ase granules Peroxidase granules Nucleus with visible Chromosomes ready to Divide.

  5. Myelodysplasia (MDS)History and nomenclature • As early as 1938 “ refractory anemias “ were worrying hematologists, since they saw that they were “ preleukemic states “. • In the 1950-ies Dameshek described and classified “ Myeloproliferative Disorders “ the way we still do now. • Somewhat related but with Pancytopenia and rarely huge splenomegaly myelodysplasias were recognized and classified in the 1970 –ies .

  6. FAB classification of MDS and Myeloproliferative ( MPD ) disorders. • MDS MPD • Refractory Anemia ( RA ) Polycythemia Vera ( PV ) • Refractory Anemia with Essential Thrombocthemia (E T ) Sideroblasts ( RAS ) Idiopathic Myelofibrosis with • Refractory Anemia with Myeloid Metaplasia (MF) Excess of Blasts ( RAEB ) • Refractory Anemia with Chronic Myelogenous Leukemia Excess of Blasts in transformation (CML) ( RAEB – T ) • Chronic Myelo-Monocytic Chronic Myelo-Monocytic Leuk Leukemia ( CMML ) ( CMML ) Acute Myeloid or Monocytic leuk.

  7. Myelodysplasia Patient presentations • Patient No.1 : 2005 – 51 year old fire fighter previously healthy, Exposed to the large tire fire in Hagersville in late 90 – ies. Ref. for fatigue and Pancytopenia. Past Hx. Not contributory. Family Hx : no neoplasias. Funct. Enq. : fatigue and easy bruising. Phys. Exam: tall, fit, slim. No nodes, no hep-spl.megaly. Lung, CVS, abdomen, CNS – intact.

  8. Myelodysplasias (MDS)Patient presentations 2 (cont.) • Pt. No.1: Investigations: • Leucocytes : 2.8; N – 1.3, Ly – 1.2, Mono – 0.3 • Hb. -120 g/l; MCV -102, ; Platelets – 92 X 10^9 / l • B12 – 604, , Folate – 1,200, • Creatinine -95, Uric Acid – 380, Ferritin – 420, ; LFT – N. • Prot. Eph.- N. ; Quantit. Immunoglob. – N, ANA – Neg. • Urine – N, Direct and Indirect Coombs’ – Neg. • Bone Marrow –Myeloid hyperplasia, Nucleo-cytoplasmic asynchrony. Hemosiderin – 3+/6. • Cytog. –del. 5q ( 5q - ). Pt counselled. Ref. to MUMC for Lenalidomide ( Revlimid ) therapy. 4 yrs later in CR

  9. Myelodysplastic bone marrow – Patient No.1

  10. Myelodysplasia : Bone marrow hemosiderin with ringed sideroblasts

  11. Myelodysplasia (MDS) : Patient No. 2 • 1993 – 58 year old female, mother of 3. • Ref. for: fatigue, recurrent sore throats, colds, UTI-s , Pancytopenia. • Past Hx : Heavy smoker, developed bladder Ca. Treated with intravesical chemotherapy for several months and BCG. • Exam: pallor, few submandibular and cervical nodes, firm, mobile, non tender, tip of spleen. Lungs clear, CVS – Reg.S1-S2, systolic ejection M.2/6 over entire precordium. MSK, CNS – intact. Integument – ecchymoses on shins.

  12. Myelodysplasia (MDS): Pt. No 2 ( cont. ) • Pertinent Labs: Hb.-108, MCV- 92 Lc -3.2, N- 0.6, Ly – 1.2, Mono – 1.2, Blasts – 0.4, Plat. -76 X 10^9 / l . B12 , folate – N., Creatinine – 75, Ferritin – 700, Urine – RBC-s in sediment. LFT- N., ANA – Neg., Coombs’ – Neg. B.M – Myeloid hyperplasia, blasts – 12%, Hemosiderin – ring sideroblasts. Cytogenetics – multiple nonspecific anomalies. Diagnosis – RAEB –T Therapy: Allopurinol, Cytosar subcut., + 6TG. Went in less than 3 mos. Into AMML , refractory, died.

  13. Myelodysplasia : Bone Marrow with ringed sideroblasts Pt. No.2

  14. Acute Myelo-Monocytic Leukemia

  15. Myelodysplasia (MDS): Patient No.3 • 2004 – 91 year old Italian Canadian male. • Ref. for anemia and severe fatigue and dyspnea. • Past Hx: worked in steel plant for 30 years with little or no protective clothing. Smoked and drank wine all his life. • Exam: PALLOR, no nodes, large spleen- visible and palpable 9.0 cm BCM. Liver edge also palp. Crrackles at both lung bases.

  16. Myelodysplasia (MDS): Patient No. 3 (cont.) • Pertinent Labs: Hb. 78 g/l, MCV -103, Leucoc. -17,600, N- 8,000, Mono – 7,600, Ly- 1,800, Eos – 200. Plat. 112,000. Leuco-Erythroblastic PB blood picture. Uric Acid – 550 . • Bone Marrow: Heavy myelo-Monocytic infiltration. Cytogenetics – Deletion of Y chromosome. (-Y) • Therapy: Refused chemotherapy. • Rx : Allopurinol. • Regular blood transfusions 1 X /month X 5 years.

  17. MDS/ MPD – Chronic Myelo-Monocytic Leukemia

  18. How frequent is MDS ? • Prevalence: • 10,000 new cases /year in USA, compared to: • 2.1 / 100,000 AML • 4.1 / 100,000 MDS • Incidence increases with age: • 0.5/100,000 in individuals < 50 years, • 5.3/100,000 “ “ 50 - 59 years • 15.0/100,000 “ “ 60 - 69 “ • 49.0/100,000 “ “ 70 -79 “ • 89.0/100,000 “ “ > 89 “

  19. MDS in children and youth • Rare in kids, median age 6 years. • Juvenile CMML: splenomeg., leucocytosis, monocytosis, polyclonal gammopathy. Thrombocytopenia, skin involvement. • Monosomy 7 (-7 ) syndrome: susceptibility to AML, frequent infections, familial tendency. • Congenital Fanconi’s Pancytopenia: megaloblastoid BM, skeletal and renal anomalies. • Aplastic or hypoplastic MDS +/- PNH

  20. Fanconi’s congenital and familial Pancytopenia

  21. Hypoplastic MDS in Fanconi’sPancytopenia

  22. MDS : Clinical and lab. characteristics • Early on asymptomatic and incidentally discovered as anemia or multilineage cytopenia. • Anemia symptoms: fatigue, dyspnea, palpitations, dizziness, angina, CHF, slowing of mental processes. • Leuco-Neutropenia: also impaired chemotaxis, phagocytosis, bactericidal activity, often skin inf. • Thrombocytopenias and impaired hemostasis. • Paraneoplastic autoimmune manifestations: vasculitis, arthritis, edema, pulm. Infiltrates, pleural and peric. Effusions, iritis, myositis, skin ulcers , chloromas, neuropathies, • Acquired Pure Red Cell Aplasia

  23. MDS – Laboratory characteristics • Normo – or – macrocytic anemia, aniso-poikilocytosis. • Normal B12, folate. • Leuco-erythroblastosis may be present, when MDS advanced. • Basophilic stippling, Howell-Jolly bodies, giant bands and hypogranular granuloc., Pelger-Huett anomaly, hypersegmentation. • BM – hypercell., megaloblastoid = nucleo-cytoplasmic asynchrony, micro- and- very polyploid megakaryocytes. • PNH – like defects in RBC-s ( CD55 and CD59 )-high complement sensitivity.

  24. MDS – Lab. Characteristics continued • Lymphopenia, esp. CD 4 after many transf., elev. CD 8 • Hypo-or – hypergammaglob. • MGUS – especially with CMML • Lympho-plasmacytic neoplasms may coexist or follow. • Occas. Myelofibrosis – on BM biopsy due to PDGF- alpha with pos. JAK 2 617F (MPD cytog. Feature) • Immuno-cytochemistry: Myeloperoxidase in myeloid cells. • Alpha Naphtyl Esterase in Monocytes, • CD 13, CD 14, CD33 - in myeloid precursors • Antibodies to F.VIII & v.W.F in Megakaryocytes.

  25. MDS – Necessary diagnostic criteria • 1. Persistent, unexplained cytopenia with the known morphologic anomalies. • 2. Older adults with normo- or – macrocytic anemia without B12, folate deficiency. • 3. Hyper ( rarely hypo ) cellular BM with megaloblastoid and asynchronous maturation features. Ineffective hematopoiesis. • 4. Cytogenetic anomalies in 40-60% of pts.: 5q -; 7 – etc. • 5. Blast count: Myeloblasts or monocytes over 1,000 / ul., CD34 is proof of blast, but not all blasts are CD 34 +.

  26. MDS – Differential diagnosis • 1. Anemia of the “ Elderly “ – probably no such entity, since even at a cellularity of 30 % with adequate substrates of : Albumin, Fe++, B12, Folate, BM is capable of increasing its production up to 6 X basal, in the absence of • 2. Chronic Inflammatory, neoplastic, renal hepatic orthyroid and other endocrine disease. • 3. MDS often accompanies in elderly other comorbidities, which render diagnosis and therapy quite difficult.

  27. MDS – Differential diagnosis continued • 4. PNH clones may be found in both MDS and Aplastic Anemia (AA) These type of MDS may respond to immunosuppression ( steroids and ATG ) AA treated may recover with clonal hematopoiesis, develop PNH, MDS and finally AML • 5. MDS with Myelofibrosis (MDS-F ) • 6. Acute Megakaryocytic Leukemia (M7 by FAB) accomp. By fibrosis and branching reticulin. • 7. Acute Panmyelosis with Fibrosis (APMF) – up to 20-25 % blasts in BM, dysplasia and pancytopenia.

  28. MDS – WHO classification

  29. MDS – International Prognostic Scoring System ( IPSS) SCORE • 1. Blasts • 5% or less 0.0. • 5-10% 0.5 • 11 – 20 % 1.5 • 21 – 30 % 2.0 • 2. Cytogenetics • A. Good : 5q -; 20 q - ; Y – 0.0 • B. Intermediate : Any other anomaly 0.5 • C. Poor : > 3 anomalies ; Monosomy 7 ; • Trisomy 8 ( 8 + ) 1.0

  30. MDS – International Prognostic Scoring System ( IPSS ) continued Score • 3. Cytopenias • Leucoc. < 1,800/ul 0.0 • Hemoblobin < 100 g/l 0.5 • Platelets < 100.000/ul 2/3 • A. Low Risk Group 0.0 • 50% survival 5.7 yrs • 25% develop AML in 9.4 yrs. • B. Intermed. Risk I - 0.5 • 50% survival 3.5 yrs. • 25% develop AML in 3.3 yrs

  31. MDS – IPSS continued Score • C.Intermed. Risk II 1.5 – 2.0 • 50% survival one year • 25% develop AML within one year • D. High Risk Group > 2.0 • 50% survival 4.5 months • 75% develop AML during that time

  32. Myelodysplasia (MDS) Clinical Issues • MDS present with significant clinical and biological heterogeneity. • Considerable variability among pts. Of the same subtype. • There are very different outcomes in pts. Assigned to the same IPSS. • MDS is not static and changes occur over months and years in the same pt. • Comorbid medical problems in elderly complicate MDS and aggravate prognosis. • MDS is often underdiagnosed: anemia attributed to chr. Inflamm., renal , other neoplastic disease or advancing age.

  33. Myelodysplasia (MDS)Etiopathogenesis. • 1. Genetic somatic mutations and abnormal DNA repair, more frequent as age advances, • 2. Heritable predisposition: • Fanconi’s Pancytopenia, • Congenital Neutropenia ( Schwachman-Diamond ) • Down Syndrome ( trisomy 21 ) • Familial Monosomy 7 (7 - ) • Trisomy 8 Mosaicism ( 8 + ) • Neurofibromatosis. etc

  34. Myelodysplasia (MDS)Etiopathogenesis (cont.) • 3. Acquired: • Vit. B12 and /or folate deficiency, +/- chr. Liver dis. • Chemotherapy : Alkylators – mutagenic, antimetabolites e.g. – Methotrexate, Purine – 6MP or Pyrimidine DNA intercalators • Radiation – therapeutic or nuclear ( Chernobyl 1986 ) • Benzene and its derivatives, • Bone Marrow conditioning and transplantation, • Paroxysmal Nocturnal Hemoglobinuria (PNH) with clonal expansion of cells hypersensitive to Complement.

  35. MDS – Mechanisms of ineffective Hematopoiesis : early apoptosis in B.M. • “Intrinsic mechanism” “Extrinsic Mech.” Mitochondria Cytochrome C Caspases Cytotoxic T - cell Death ligands Death receptors : Fas, TNF-R Trail Oncoprotein ratios BM Microenvironment MDS Clone

  36. Myelodysplasia - Therapy • A. Supportive • Early stage and low IPSS do not require treatment for some time if slowly evolving. • RBC Transfusions according to symptoms: • Hb.< 90 g/l in elderly will cause dyspnea, angina, CHF. • EPO and G-CSF have been used succesfully in a series of pts., but on occasion have accelerated leukemic transformation.

  37. Myelodysplasia – Therapy ( cont. ) • Complications of transfusions: • 1. Iron overload : each Unit of PRBC-s of ~ 250 ml contains 250 mg of Fe++. • In addition – ineffective erythropoiesis with ring sideroblasts in the mitochondria, causes also unutilized Fe++ in the RES. – liver, spleen, BM, heart and pancreas – hemosiderosis . • Canadian guide lines recommend Iron chelation therapy when Ferritin reaches 1,000. • 2. Alloimmunization due to repeat transfusions is bound to occur. • T 4 lymphopenia occurs after repeat transfusions.

  38. Myelodysplasia - chemotherapy • Hypomethylating agents – DNA binding / competing: 5 Azacytidine and recently – Decytabine ( Dacogen ) • Anti-angiogenic – related to Thalidomide – Lenalidomide ( Revlimid ) – very effective in 5q- syndrome. • Allogeneic stem cell transplant with moderate conditioning regimen has been successful in 5q - , as well as in overlap MDS-MPD even in elderly vigorous septagenerians. • Immune suppression in Hypoplastic MDS with ATG has been also succesful.

  39. MDS – St.Joe’s Retrospective review of 60 charts2004 - 2008 • 1. AGES : 39 - 94 years. • Average : 74.2 • Median : 78.7 • Young : between 39 and 68 years – 9 pts . • 2. GENDER : 29 - Males; 31 - Females.

  40. MDS – St. Joe’s :Retrospective review 2004 – 2008 60 charts. • DIAGNOSES: • 1. Refractory Anemia (RA) – 5 ; one – 5q – • 2. Refractory Anemia with Ring Sideroblasts (RAS) – 2 • 3. Refractory Anemia with Excess of Blasts (RAEB) – 3 ; one 5q – • 4. Refractory Anemia with Excess of Blasts in Transformation (RAEB – T) – 5 • 5. RA with Multilineage Dysplasia - 16

  41. MDS – St. Joe’s : Retrospective Review 2004 – 2008 60 charts • 6. MDS – Undefined – 10 ; One - Trisomy 15, Y- ; One – Loss of X chromosome. • 7. MDS – MPD overlap syndrome – 3. These were JAC 2 – Neg., BCR-ABL – Neg., one had a picture of Polycythemia Vera and LAP = 183 ( Normal up to 130 ) • 8. Chronic Myelo-Monocytic Leukemia (CMML) – 14 patients • 9. Acute Myelog. Leukemia (AML) from MDS – one patient .

  42. MDS – St.Joe’sRetrospective Review 2004 -200860 charts

  43. MDS – at St. Joe’sRetrospective Review 2004 – 2008Comorbidities for admission • G – I bleeds due to thrombocytopenia +/- anticoagulants for atrial fibrillation, • CHF – due to anemia; Ac. Coronary syndr. • Preceding or concomitant neoplasias : breast, esophagus, colon etc. • MGUS; previously treated Myeloma. • Severe infections and often septicemia. • Autoimmune diseases: vasculitis, Rheum. Arthritis, Chr. Renal disease and failure. • Ferritin in two patients: 2,000 and 3,500

  44. Myelodysplasia – Summary and Conclusions • 1. MDS are quite frequent in aging populations, but are occas. present in young persons and children. • 2. Since MDS involves the pluripotential stem cell, any or all hematopoietic progenitors may be affected. • 3. MDS in elderly is often accompanied by comorbidities, thus detracting our attention from symptoms and signs of MDS – cause of anemia, bleeding tendency, recurrent infections.

  45. Myelodysplasia – Summary and Conclusions ( cont. ) • 4. The biology and evolution of MDS depends on a variety of factors: • Subtype of MDS, • IPSS • Patient’s age and physical condition but mainly • Comorbidities. • 5. In patients with severe and irreversible comorbidities supportive therapy is compelling. • In healthier constitutions, chemotherapy should be considered and even stem cell transplant with curative intent.

  46. Thank You Thank you for your attention

  47. MDS – St.Joe’s:Retrospective Review : 2004 -200860 charts.

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